Visceral adiposity is a major risk factor for the development of insulin resistance, type 2. diabetes and its co-morbidities of dyslipidemia and cardiovascular disease. Adipose tissue has been recognized to be an important endocrine organ that regulates energy homeostasis, glucose and lipid metabolism via adipokines like leptin and adiponectin, fatty acid release and possibly neuronal afferens. Insulin and leptin are two of the major adiposity hormones that have been shown to regulate food intake and glucose fluxes to a large extend via central, i.e. brain signaling. While leptin decreases adiposity, insulin increases lipid storage in adipose tissue chiefly by suppressing lipolysis. The inhibition of lipolysis by insulin is believed to be mediated exclusively by insulin signaling in adipocytes. The brain control of adipose tissue metabolism via the autonomic nervous system is poorly understood. Previous work from our lab has demonstrated that leptin suppresses lipogenesis and induces lipolysis in adipose tissue via the medio-basal hypothalamus (MBH) and requires intact sympathetic innervation of adipose tissue. Since insulin exerts the opposite physiological effects on adipose metabolism then insulin, we speculated that part of insulins prolipogenic and antilipolytic effects are mediated by brain insulin signaling. Indeed, we have made the novel observation that insulin infused into the third ventricle or the MBH potently suppresses whole body and adipose tissue lipolysis and induces adipose tissue lipogenic protein expression independent of changes in circulating insulin and glucose levels or food intake. Thus, the central hypothesis of our proposal is that leptin and insulin exert opposing effects on visceral adipose tissue metabolism. We wish to characterize the central and peripheral pathways that participate in the brain control of adipose tissue metabolism and lipid fluxes in physiological and pathophysiological (dietary, inflammatory and genetic insulin resistance) contexts to understand if impaired brain control of adipose tissue metabolism contributes to the unrestrained lipolysis in the insulin resistant state. These studies should advance our understanding of how the brain controls WAT metabolism and adiposity independent of food intake by regulating nutrient partitioning. PUBLIC HEALTH RELEVANCE: Visceral adiposity is a major risk factor for the development of insulin resistance, type 2 diabetes and its co-morbidities of dyslipidemia and cardiovascular disease. Here we provide evidence that the two major adiposity hormones leptin and insulin regulate visceral adiposity and lipolysis via the brain. The goal of the proposed studies is to mechanistically explore the central signaling pathways involved and the relay mechanism that exert this brain control of adipose tissue metabolism and whether impaired brain control of lipolysis contributes to insulin resistance and type 2 diabetes.